Tsatsanis C, Fulton R, Nishigaki K, Tsujimoto H, Levy L, Terry A, Spandidos D, Onions D, Neil J C
Department of Veterinary Pathology, University of Glasgow, Bearsden, Scotland.
J Virol. 1994 Dec;68(12):8296-303. doi: 10.1128/JVI.68.12.8296-8303.1994.
The genetic basis of feline leukemia virus (FeLV)-induced lymphoma was investigated in a series of 63 lymphoid tumors and tumor cell lines of presumptive T-cell origin. These were examined for virus-induced rearrangements of the c-myc, flvi-2 (bmi-1), fit-1, and pim-1 loci, for T-cell receptor (TCR) gene rearrangements, and for the presence of env recombinant FeLV (FeLV-B). The myc locus was most frequently affected in naturally occurring lymphomas (32%; n = 38) either by transduction (21%) or by proviral insertion (11%). Proviral insertions were also common at flvi-2 (24%). The two other loci were occupied in a smaller number of the naturally occurring tumors (fit-1, 8%; pim-1, 5%). Examination of the entire set of tumors showed that significant numbers were affected at two (19%) or three (5%) of the loci. Occupation of the fit-1 locus was observed most frequently in tumors induced by FeLV-myc strains, while flvi-2 insertions occurred with similar frequency in the presence or absence of obvious c-myc activation. These results suggest a hierarchy of mutational events in the genesis of feline T-cell lymphomas by FeLV and implicate insertion at fit-1 as a late progression step. The strongest links observed were with T-cell development, as monitored by rearrangement status of the TCR beta-chain gene, which was positively associated with activation of myc (P < 0.001), and with proviral insertion at flvi-2 (P = 0.02). This analysis also revealed a genetically distinct subset of thymic lymphomas with unrearranged TCR beta-chain genes in which the known target loci were involved very infrequently. The presence of env recombinant FeLV (FeLV-B) showed a negative correlation with proviral insertion at fit-1, possibly due to the rapid onset of these tumors. These results shed further light on the multistep process of FeLV leukemogenesis and the relationships between lymphoid cell maturation and susceptibility to FeLV transformation.
在一系列63个假定为T细胞起源的淋巴样肿瘤和肿瘤细胞系中，研究了猫白血病病毒（FeLV）诱导淋巴瘤的遗传基础。检测这些样本是否存在病毒诱导的c-myc、flvi-2（bmi-1）、fit-1和pim-1基因座重排、T细胞受体（TCR）基因重排以及env重组FeLV（FeLV-B）的存在情况。在自然发生的淋巴瘤中（32%；n = 38），myc基因座受影响最为频繁，其中转导（21%）或前病毒插入（11%）所致。前病毒插入在flvi-2基因座也很常见（24%）。另外两个基因座在较少数量的自然发生肿瘤中被占据（fit-1，8%；pim-1，5%）。对所有肿瘤的检查表明，相当数量的肿瘤在两个（19%）或三个（5%）基因座受到影响。在由FeLV-myc株诱导的肿瘤中，fit-1基因座的占据最为常见，而无论c-myc是否明显激活，flvi-2插入的发生频率相似。这些结果表明，FeLV诱导猫T细胞淋巴瘤发生过程中存在一系列突变事件，并提示fit-1基因座的插入是晚期进展步骤。观察到的最强关联是与T细胞发育相关，通过TCRβ链基因的重排状态监测，其与myc激活呈正相关（P < 0.001），与flvi-
